The identification of potential tumor rejection antigens recognized by autologous T cells has spawned numerous clinical trials that target melanoma cells expressing these antigens. Adoptive T cell therapy, involving the isolation and ex vivo expansion of antigen-specific T cell clones for infusion provides for rigorous control over the magnitude, specificity and phenotype of the intended immune response so that the requirements for successful tumor eradication can be clearly defined. Preliminary results using this approach for the treatment of patients with metastatic melanoma in a Phase I clinical trial have demonstrated that adoptive T cell therapy using antigen-specific CD8+ CTL clones, persist in vivo, traffic to tumor sites and can mount a specific immune response with favorable clinical outcomes. Obstacles to more effective therapy were found to be a limited duration of in vivo persistence that was only partially extended with low-dose IL-2. Due to the counter-regulatory effects and cumulative toxicities of IL-2 with prolonged administration, an alternative strategy would be highly desirable. Based on the observation that CD8+ T cells undergo homeostatic proliferation and expansion in a lymphodepleted host, we propose to evaluate in a Phase I clinical trial, the safety, duration of in vivo persistence and anti-tumor effect of adoptively transferred CD8+ antigen-specific CTL clones following fludarabine-mediated lymphodepletion in patients with metastatic melanoma.